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通过膜透的特诺福维尔二和单酸盐类似物

Xiao Jia¹, Giuliano A Kullik¹, Marianna Bufano²

¹Organic Chemistry, Department of Chemistry, Faculty of Mathematics, Informatics and Natural Sciences, Universität Hamburg, Martin-Luther-King-Platz 6, D-20146, Hamburg, Germany.

European journal of medicinal chemistry

|December 12, 2023

概括

研究人员开发了用于抗病毒治疗的新型非循环核酸类似物 (ANP) 和前期药物. 这些化合物表现出强烈的抗HIV活性,其中一种衍生品在细胞模型中显著提高了疗效和安全性.

科学领域:

药用化学医学化学
病毒学病毒学
有机合成有机合成

背景情况:

持续需要新型抗病毒药物,特别是核酸和非循环核酸类似物 (ANP).
开发前药物来增强抗病毒化合物的稳定性和输送.

研究的目的:

合成新型脂性三酸盐和 (R) -PMPA的二基化二酸盐类似物.
评估这些新化合物的稳定性,选择性释放和抗病毒活性.

主要方法:

合成三种类型的脂性三酸盐和 (R) -PMPA的二基化二酸盐类似物.
从前药物中选择性释放核酸相似物的评估.
在PBS,细胞提取物和人体血中进行稳定性研究.
使用HIV-RT和人类聚合酶 γ 的初级扩展试验.
在HIV-1/2感染细胞系 (CEM/0和CEM/TK−) 中进行抗病毒疗效测试.

主要成果:

从合成的前药物中获得 (R) -PMPA-DP, (R) -PMPA-MP和 (R) -PMPA的高度选择性释放.
基化 (R) -PMPA原药在各种生物介质中表现出极好的稳定性.
单基和二基基化 (R) -PMPA-DP衍生物作为HIV-RT的基质,但不是人类聚合酶 γ.
基化 (R) -PMPA化合物显示出显著的抗HIV疗效.
衍生物9a (二基化 (R) -PMPA-MP) 显示出对HIV-2的326倍改善,高选择性指数 (SI) 为14.000.

结论:

合成的二甲基化 (R) -PMPA类似物是稳定且有效的前体药物.
这些化合物表现出强有力的和选择性的HIV复制抑制.
这项研究对基于核酸模拟的抗病毒药物的进展做出了重大贡献.

关键词:

抗病毒化合物抗病毒化合物 DNA聚合酶是一种DNA聚合酶.核酸核酸是一种核酸.一个药物产品.逆转录酶的使用方法三酸三酸盐的使用方法

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